Neutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL-induced osteoclastogenesis

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dc.creatorAyda Henriques Schneider
dc.creatorRenê Donizeti Ribeiro de Oliveira
dc.creatorThiago Mattar Cunha
dc.creatorJosé Carlos Alves-Filho
dc.creatorPaulo Louzada-Júnior
dc.creatorTarcília Aparecida da Silva
dc.creatorSandra Yasuyo Fukada Alves
dc.creatorFernando de Queiroz Cunha
dc.creatorThaise Mayumi Taira
dc.creatorGabriel Azevedo Públio
dc.creatorDouglas da Silva Prado
dc.creatorPaula Barbim Donate Yabuta
dc.creatorJéssica Cristina Dos Santos
dc.creatorCaio Cavalcante Machado
dc.creatorFlávio Falcão Lima de Souza
dc.creatorLucas Gabriel Rodrigues Venturini
dc.date.accessioned2025-05-20T23:23:13Z
dc.date.accessioned2025-09-09T00:15:22Z
dc.date.available2025-05-20T23:23:13Z
dc.date.issued2024-02
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.description.sponsorshipFAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1111/bph.16227
dc.identifier.issn1476-5381
dc.identifier.urihttps://hdl.handle.net/1843/82394
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofBritish Journal of Pharmacology
dc.rightsAcesso Restrito
dc.subjectOsteogenesis
dc.subjectExtracellular traps
dc.subjectOsteoclasts
dc.subjectArthritis, rheumatoid
dc.subjectRANK Ligand
dc.subjectProtein-arginine deiminase type 4
dc.subjectDeoxyribonucleases
dc.subjectOsteoprotegerin
dc.subjectToll-like receptor 4
dc.subjectToll-like receptor 9
dc.subjectBone resorption
dc.subjectOsteoblasts
dc.subject.otherNETs
dc.subject.otherBone damage
dc.subject.otherOsteoclastogenesis
dc.subject.otherOsteoclasts
dc.subject.otherRheumatoid arthritis
dc.titleNeutrophil extracellular traps mediate bone erosion in rheumatoid arthritis by enhancing RANKL-induced osteoclastogenesis
dc.typeArtigo de periódico
local.citation.epage446
local.citation.issue3
local.citation.spage429
local.citation.volume181
local.description.resumoBackground and Purpose:Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause bone erosion due to increased osteoclastogenesis. Neutrophils involvement in osteoclastogenesis remains uncertain. Given that neutrophil extracellular traps (NETs) can act as inflammatory mediators in rheumatoid arthritis, we investigated the role of NETs in stimulating bone loss by potentiating osteoclastogenesis during arthritis. Experimental Approach: The level of NETs in synovial fluid from arthritis patients was assessed. Bone loss was evaluated by histology and micro-CT in antigen-induced arthritis (AIA)-induced WT mice treated with DNase or in Padi4-deficient mice (Padi4flox/flox LysMCRE). The size and function of osteoclasts and the levels of RANKL and osteoprotegerin (OPG) released by osteoblasts that were incubated with NETs were measured. The expression of osteoclastogenic marker genes and protein levels were evaluated by qPCR and western blotting. To assess the participation of TLR4 and TLR9 in osteoclastogenesis, cells from Tlr4−/− and Tlr9−/− mice were cultured with NETs. Key Results: Rheumatoid arthritis patients had higher levels of NETs in synovial fluid than osteoarthritis patients, which correlated with increased levels of RANKL/OPG. Moreover, patients with bone erosion had higher levels of NETs. Inhibiting NETs with DNase or Padi4 deletion alleviated bone loss in arthritic mice. Consistently, NETs enhanced RANKL-induced osteoclastogenesis that was dependent on TLR4 and TLR9 and increased osteoclast resorptive functions in vitro. In addition, NETs stimulated the release of RANKL and inhibited osteoprotegerin in osteoblasts, favouring osteoclastogenesis. Conclusions and Implications: Inhibiting NETs could be an alternative strategy to reduce bone erosion in arthritis patients.
local.identifier.orcidhttps://orcid.org/0000-0003-2474-2773
local.identifier.orcidhttps://orcid.org/0000-0003-0229-6864
local.identifier.orcidhttps://orcid.org/0000-0002-7855-3700
local.identifier.orcidhttps://orcid.org/0000-0002-9918-8714
local.identifier.orcidhttps://orcid.org/0000-0003-2585-3870
local.identifier.orcidhttps://orcid.org/0000-0001-9623-7835
local.identifier.orcidhttps://orcid.org/0000-0002-6589-4784
local.identifier.orcidhttps://orcid.org/0000-0003-4755-1670
local.identifier.orcidhttps://orcid.org/0000-0003-3719-9503
local.identifier.orcidhttps://orcid.org/0000-0002-5643-409X
local.publisher.countryBrasil
local.publisher.departmentFAO - DEPARTAMENTO DE CLÍNICA
local.publisher.initialsUFMG
local.url.externahttps://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.16227

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